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Review
. 2022 Mar 11;12(3):240.
doi: 10.3390/metabo12030240.

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

William Durante  1
Affiliations
Review

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy

William Durante. Metabolites. .

Abstract

Coronavirus disease 2019 (COVID-19) represents a major public health crisis that has caused the death of nearly six million people worldwide. Emerging data have identified a deficiency of circulating arginine in patients with COVID-19. Arginine is a semi-essential amino acid that serves as key regulator of immune and vascular cell function. Arginine is metabolized by nitric oxide (NO) synthase to NO which plays a pivotal role in host defense and vascular health, whereas the catabolism of arginine by arginase to ornithine contributes to immune suppression and vascular disease. Notably, arginase activity is upregulated in COVID-19 patients in a disease-dependent fashion, favoring the production of ornithine and its metabolites from arginine over the synthesis of NO. This rewiring of arginine metabolism in COVID-19 promotes immune and endothelial cell dysfunction, vascular smooth muscle cell proliferation and migration, inflammation, vasoconstriction, thrombosis, and arterial thickening, fibrosis, and stiffening, which can lead to vascular occlusion, muti-organ failure, and death. Strategies that restore the plasma concentration of arginine, inhibit arginase activity, and/or enhance the bioavailability and potency of NO represent promising therapeutic approaches that may preserve immune function and prevent the development of severe vascular disease in patients with COVID-19.

Keywords: COVID-19; arginase; arginine; endothelial dysfunction; immunopathology; nitric oxide synthase; thrombosis; vascular disease.

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Conflict of interest statement

The author declares no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Outline of arginine metabolism via four distinct enzymatic pathways. Arginine catabolism in immune and vascular cells is largely driven by the enzymes nitric oxide synthase (NOS) and arginase (ARG). ADC, arginine decarboxylate; AGAT, arginine-glycine amidinotransferase; ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; GAMT, guanidinoacetate N-methyltransferase; ODC, ornithine decarboxylase; OAT ornithine aminotransferase; P5CR, pyrroline-5-carboxylate reductase; P5CD, pyrroline-5-carboxylate dehydrogenase.
Figure 2
Figure 2
Targeting arginine in COVID-19-induced immune and vascular dysfunction. There is an upregulation of arginase 1 (ARG1) by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that diminishes circulating arginine levels and shunts the metabolism of arginine away from the synthesis of nitric oxide (NO) by NO synthase toward the production of ornithine, which is subsequently converted to polyamines and proline via the action of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT), respectively. The induction of ARG1 causes immune malfunction, inflammation, and endothelial cell (EC) death and dysfunction, and stimulates vascular smooth muscle cell (SMC) proliferation, migration, collagen synthesis, and platelet aggregation, leading to vasoconstriction, thrombosis, arterial thickening, fibrosis, and stiffening. Collectively, these actions will promote vascular occlusion and organ failure. Several strategies may be used to target arginine in COVID-19. Dietary supplementation with arginine or citrulline provides a forthright approach to restore circulating levels of arginine in SARS-CoV-2-infected patients. Alternatively, the use of ARG inhibitors provides a more selective modality in correcting disturbances of arginine metabolism in COVID-19. In addition, the direct administration of arginine metabolites (inhaled NO, NO donors, inorganic nitrates, and homoarginine) or NO-potentiating drugs [soluble guanylate cyclase (sGC) activators or stimulators, and phosphodiesterase type 5 (PDE5) inhibitors] affords another avenue in treating COVID-19 patients. eNOS, endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase.
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